The identification of distinct monocyte/macrophage populations that carry virus to the CNS and subsets within the CNS that are the target for infection by HIV/SIV is not defined In this study we have used immunohistochemistry and combined immunohistochemistry with in situ hybridization to define which populations of brain macrophages are infected at peak viremia and in SIVE Perivascular brain macrophages and the resident brain macrophage, microglia, are both CDllb and CD68 positive The perivascular macrophages, but not microglia, are also positive for CD14, CD45, and CD86 Multi-nucleated giant cells (MNGC), when present, are CD11b and CD68 positive like parenchymal microglia and perivascular macrophages The MNGC also are CD14 and CD45 positive, but express variable to non-detectable levels of CD4 Using combined immunohistochemistry and in situ hybridization and/or double label immunohistochemistry for myeloid cell markers followed by gp120, we demonstrat e th at the majority of gp120 or viral RNA positive cells are CD14 positive perivascular macrophages These perivascular cells are the major cell infected within the CNS during peak viremia (2 weeks post infection) and in animals with SIVE Less than 1% of the infected cells are resident microglia based upon immunohistochemistry These data underscore the importance of the perivascular macrophage as the major target of SIV in the CNS